# Impact of recurrent genetic alterations on SCLC subtypes and therapeutic response

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $351,713

## Abstract

Project Summary
Small cell lung cancer (SCLC) is a highly aggressive malignancy with high heterogeneity and few available
treatment options. SCLC cells are of highly plastic enabling them to adapt and change characteristics in
response to chemotherapy and radiation therapy. This project aims to interrogate therapeutic responses that
targeting replication stress, hallmark of SCLC. Specifically, we will establish novel SCLC animal models, with
co-mutations that identified in the clinic responsible for the development, progression, or drug resistance. To
do that, we will use establish SCLC lines with P53 and RB1 mutation, two most common mutations found in
SCLC that serve as intrinsic factor responsible for replication stress, and introduce co-mutations including
MYC, KMT2D, and/or the STK11/PTEN etc. We hypothesized that c-MYC, YAP1, PTEN, STK11, KMT2D,
p130 dysregulation may contribute to SCLC heterogeneity, replication stress, and will affect tumor growth. We
will evaluate in these models, the impact of co-mutations toward the treatment of CDK2 and/or PARP
inhibitors. In addition, we will further delineate, the cancer cell intrinsic versus extrinsic effect upon drug
treatment using state-of-art immune competent SCLC models. Finally, we will further explore the possibility of
combinational treatment of targeted drugs with immunotherapy drugs in SCLC models with different co-
mutations. To test our hypotheses, we propose the following interrelated Specific Aims: (1) To investigate
the impact of the co-mutations on SCLC plasticity and transcriptional subtypes of SCLC; (2) To evaluate the
impact of co-mutations on the responses to CDK2 and PARP inhibition responses in SCLC; and (3) To
elucidate the impact of co-mutations on the SCLC tumor immune microenvironment (TIM) and sensitivity to
immunotherapeutic combinations. Project 4 is integrated cohesively with Projects 1, 2 and 3, and Cores A, B
and C, permitting innovative and synergistic approaches and quick breakthroughs in moving basic science
discoveries to translational therapeutic strategies. IMPACT: By investigating a new scientific direction in this
P01 through pioneering work on the co-genetic alterations and pre-clinical studies, we will develop new
mechanistic insights into biological mechanisms of SCLC replication stress that can be translated into clinically
relevant therapies for patients.

## Key facts

- **NIH application ID:** 10848848
- **Project number:** 1P01CA288368-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Kwok Kin Wong
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $351,713
- **Award type:** 1
- **Project period:** 2024-08-16 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848848

## Citation

> US National Institutes of Health, RePORTER application 10848848, Impact of recurrent genetic alterations on SCLC subtypes and therapeutic response (1P01CA288368-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10848848. Licensed CC0.

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